Autacoids (Histamine, Serotonin, Ergot Alkaloids) PDF

Histamine, serotonin, Ergot alkaloids Dr. Omamah Alfarisi 2024/2025  Autacoids What are autacoids (AUTOS- self)? Autacoids are the mediators released from cells in response to various types of stimulation to generally elicit normal physi...

Histamine, serotonin, Ergot alkaloids Dr. Omamah Alfarisi 2024/2025  Autacoids What are autacoids (AUTOS- self)? Autacoids are the mediators released from cells in response to various types of stimulation to generally elicit normal physiological responses locally - they are local hormones. Their effects are related to pathological conditions such as allergy, inflammation, and ischemia reperfusion. They are structurally diverse substances produced by numerous cells, and produce different effects. Autacoids include: Amine : Histamine, 5-Hydroxtryptamine (serotonin) Eicosanoids: Prostaglandins and leukotrienes Peptides : Bradykinin, angiotensin and vasopressin Small molecules: Nitric oxide NO Histamine What is histamine Location of histamine Biosynthesis of histamine Release of histamine Mechanism of action Role in allergy and anaphylaxis Histamine receptors Antihistamines  averans Egg T Histamine distribution Histamine is a chemical mediator that mediates a wide range of cellular responses Cells that contain histamine Most of the histamine in humans is stored in: Tissue mast cells 0 ~ However, histamine can also be found in non-mast cells such as: must CNS 1. neurons of the CNS (histaminergic neurons) GI 2. gastric mucosa (histaminocytes) Baso 3. blood basophils (very small amount). Found in almost all tissue with variable amounts but mostly, in the lung, skin, GI, neurons Synthesis & storage: histidine e histamine Histamine is formed by decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase o Mast cells and basophils synthesize histamine and store it in secretory granules In non-mast cells of histamine formation (epidermis, gastric mucosa, _00 neurons) histamine is synthesized but not stored – rapid excretion Fa 1 obliggy Mechanism of histamine release The stored histamine in the mast cell can be released through several mechanisms: A. immunological release: IgE B. Chemical and Mechanical release: E  Mechanism of histamine release A. immunological release: First exposure to antigen: formation of Ig-E that binds to mast cell Second exposure: explosive 2 degranulation and release of histamine Requires Ca & energy 8 Ig-G and Ig-M also cause histamine release from mast cell Released histamine exert negative feedback mediated by H2 receptors on mast cells in the skin and blood (not lung) T vefeedback Mechanism of histamine release B. Chemical and Mechanical release: Certain amines including drugs such as morphine o and tubocurarine can displace histamine from its bound form within cells Doesn’t require energy I Not associated with mast cell injury or explosive degranulation 1a Histamine receptors Histamine produces its effects by acting on histamine receptors. Soon There are four histamine receptors sub-types H1, H2, H3 and H4. All histamine receptors are GPCRs. G protein CoupledReceptors Histamine receptors- distribution H1 H2 H3 H4 GPCR (and 2nd Gq/11 Gs Gi/o Gi/o messenger) (Ca2+,  NO, and  cAMP ( cAMP,  MAPK)  cGMP) Distribution Smooth muscle Gastric mucosa CNS: presynaptic Cells of (vascular and parietal cells, hematopoietic bronchial), cardiac muscle, origin endothelial cells, smooth muscle CNS, other types of mast cells, CNS, cells* other types of cells* *Other types of cells include epithelial and endothelial cells, neutrophils, eosinophils, monocytes, dendritic cells, T cells, B cells, hepatocytes, and chondrocytes  What are the actions of histamine? On blood vessels VD On the heart On the GIT On the airways On the skin On the sensory nerves  Pharmacologic effects of histamine iiigg iiiiiiii.ie Cardiovascular system: Vasodilation: QQi Of indirect Histamine through H1 receptors on the vascular endothelium release nitric so oxide (NO) that diffuse to vascular smooth muscle causing rapid short-lived vasodilation direct Direct Activation of H2 receptors on vascular smooth muscle causes dilation that develops more slowly and is more sustained Increased “Capillary” permeability: histamine – acting on H1 receptor on the endothelial vascular cell leads to efflux of plasma protein and fluid into the extracellular space and increase lymph flow causing edema I iiiiiii Its iii Pharmacologic effects of histamine Heart: contraction D Histamine affects both cardiac contractility and electrical events directly Histamine increases the rate and the force of contraction of the heart by its a action on cardiac H2 receptors i.e. positive chronotropic and inotropic effects Extravascular smooth muscle: Cat Histamine contraction BC asthen Bronchial: Histamine directly contracts smooth muscle mainly through H1 receptors due to increase in Ca levels. Severe bronchoconstriction in asthmatics a c Gastrointestinal tract: histamine causes contraction of GI smooth muscle. Can cause severe abdominal cramps and diarrhea I Pharmacologic effects of histamine Secretory tissue: E Histamine is a powerful stimulant of gastric acid secretion by acting on gastric parietal cells through H2 receptors Peripheral nerve endings: Histamine stimulates various nerve endings and sensory effects. In the epidermis, it causes itch. In the dermis, it evokes pain, sometimes 00 accompanied by itching. Via H1 receptor CNS: Histamine via H1 receptor is a mediator of wakefulness and alertness 7  Pharmacologic effects of histamine Skin response: The triple response of Lewis (intradermal injection of histamine): 1. Intense red spot of skin (H1 receptors) due to vasodilation 2. Flare (slight redness (erythema) in the surrounding area ( H1 receptors) 3. Wheal formation (H1 receptors) oedema  Pharmacologic effects of histamine Histamine shock (Anaphylaxis): Histamine given in large doses or released during systemic anaphylaxis causes a profound and progressive fall in blood pressure II Iliff  H1 receptor antagonist 9244 Eat 4 H1 blockers can be divided into first- and second- generation drugs tyre 1st generation anti-histamine block in addition to H1, muscarinic, , α- adrenergic, serotonin and cross the BBB This non-selectivity can be useful in some conditions but also induce adverse effects Examples: chlorphenamine, diphenhydramine, pheniramine, promethazine 6yvs 2nd generation are highly selective anti-histaminic receptor and doesn’t cross the BBB either Examples: loratadine, cetirizine, desloratadine, fexofendadine as Tm is III  pukes Uses of histamine (H1) receptor antagonists Treatment of allergic and pseudoallergic reactions (Main) and anaphylactic reactions Allergic rhinitis Atopic dermatitis Urticaria Insect bites Drug hypersensitivities reaction Why  Histamine (H1) receptor antagonists: Main effect is related to blockade of (H1) receptor on: VC Vascular smooth muscle: Within the vascular tree, H1 receptor antagonists inhibit both the vasodilator and increased permeability (edema) effects of histamine. 1 Sensory nerves (C-fibres): Histamine (H1) antagonists also inhibits the: fItch/tingle sensation in the nose (sneeze) in allergic rhinitis and the skin (pruritus)  Features of 1st generation H1 antagonists 1st generation anti-histamines are not selective to histamine receptors but also have: anti-muscarinic effects anti-dopaminergic effects as Example: diphenhydramine, chlorpheniramine, promethazine Side effects include Antimuscarinic effect: me Dry mouth, blurred vision, urinary retention and constipation occur with some drugs in some patients w̅ Marked sedation – CNS effect (due to mainly the anti-histamine central action). Should generally be avoided when driving or operating machinery or when wakefulness is necessary on e Other uses of H1 antagonists Anti-emetic: Motion sickness, morning sickness, vertigo: not related to H1 receptor inhibition (but due to anti-dopaminergic and anti- muscarinic action)- mostly promethazine Sedative: 1st generation antihistamine – sleep aid due to CNS effect OTC cough (1st generation)-  H2 Receptor Antagonists The pharmacology and clinical utility of H2 antagonists is mainly to inhibit gastric acid secretion mainly with gastric reflux or ulcers Example: ranitidine, cimetidine Serotonin Distribution 5-hydroxytryptamine I (5-HT, serotonin) is both neurotransmitter and local hormone The highest concentration of 5-HT is found in three organs: The wall of the intestine off enterochromaffin cells Nerve cells of the myenteric plexus – neurotransmitter Blood: __ In Platelets Broadly throughout the CNS see Synthesis, storage, release, degradation Synthesis: 5-HT is synthesized by a 2-step pathway from the dietary amino acid L-tryptophan in the chromaffin cells and the neurons 5-hydroxytryptamine L-Tryptophan Sydroxy L-5-hydroxytryptophan amine (serotonin, 5-HT) Storage: 5-HT is stored in intracellular storage vesicle via vesicular transporters 5 Uptake of 5-HT: (SERT) Degradation of 5-HT: I_ Platelets and neurons posses as high-affinity 5-HT uptake mechanism via active transporters occurs mainly through oxidative deamination by monoamine oxidase A (MOA) followed by oxidation to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine – used as diagnostic test Classification of 5-HT receptors 5-HT acts on large variety of 5-HT subtypes receptors (14 subtypes divided into 7 classes)- 5-HT1-7; all are GPCR except 5-HT3 ligand- gated cation channel With the exception of 5-HT3-selective agents, 5-HT receptor agonists and antagonists are relatively non-selective with respect to different receptor subtypes Classification of 5-HT receptors 5-HT1 receptors: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F 5-HT1A: Locations: CNS (presynaptic-inhibitory/ postsynaptic) Effects: activation of presynaptic neurons  inhibit excessive serotonin release  regulate mood, anxiety, and stress Partial agonists (buspirone) is used as anxiolytic 5-HT1B and 5-HT1D receptors: Locations: presynaptic neurons in the CNS smooth muscle cells in cranial blood vessels Effects: inhibition of serotonin release and vasoconstriction Triptans (5HT-1B/1D agonist) used for migraine Pharmacologic actions of 5-HT Effects on the GI tract motility: 5-HT facilitates peristalsis, intestinal motility, and secretion Due to direct action on smooth muscle plus stimulating action on ganglion cells located in the enteric nervous system Nausea and emesis: 5-HT induce nausea and emesis through activation of brain regions that control nausea: Activation of the vomit centre (VC) in the medulla region, by 5-HT, via stimulation of inputs from vagal sensory fibres in the GIT. Pharmacologic actions of 5-HT Cardiovascular effects: Effect on blood vessels: The effect of 5-HT on blood vessels depend on various factors including: size of the blood vessel, the location of the blood vessels, the sub-type of 5-HT receptor Large Vessels (Arteries and Veins): Usually constricted due to direct action on vascular smooth muscle cells (VSMCs). Small Vessels: Dilation is caused by: Release of nitric oxide (NO) Inhibition of noradrenaline from sympathetic nerve terminals. If 5-HT is injected (i.v.), BP first significantly increases due to constriction of the large vessels, and may then show a small fall because of arteriolar dilatation.  Cardiovascular effects (cont.): Platelets: 5-HT is not synthesized in platelets but uptaken, stored, and released When platelets make contact with injured endothelium: they release substances that promote platelet aggregation and secondarily they release 5-HT 5HT binds to platelet 5HT2A receptors that enhance further aggregation Some important actions of 5-HT (cont..) PNS actions: 5-HT stimulates and sensitizes nociceptive sensory nerve ending and may also result in local release of sensory neuropeptides to induce neurogenic inflammation (NI). Nausea and emesis (see earlier) CNS actions: 5-HT is known to be involved in several CNS mediated events such as migraine (NI), stress and anxiety, mood, vomiting, appetite and can induce hallucination. Cellular effects of 5-HT in the CNS depend on the receptor subtype and can cause: 1. Post synaptic excitation 2. Post synaptic inhibition 3. Pre-synaptic inhibition (autoreceptor). Clinical application for drugs targeting 5-HT CNS: conditions: Depression and anxiety Migraine: Psychosis Mixed CNS and peripheral conditions: Carcinoid syndrome Nausea/emesis Appetite Other  Migraine: role of trigeminal vascular system The trigeminal-vascular system: Function: the sensory neurons that innervate the cerebral vessels- send pain, touch, temperature sensation to the brain Pathogenesis of migraine: Triggers the release of Vasodilation Extravasation neuropeptides and of plasma and Activation of (e.g., Calcitonin inflammation proteins into Mechanical Shunting of Trigeminal Gene-Related of meningeal the Stretch: Blood Flow: Nerves: Peptide (CGRP) and cranial perivascular and Substance vessels. space. P). Resulting from Dilation can lead edema may to shunting, explain acute causing hypoxia migraine pain. and contributing to pain. Migraine treatment: 5-HT1 receptors agonists 5HT1B and 5HT1D exists on: VSMC in the meningeal arteries peripheral and central trigeminal neurons Activation of 5HT1B/1D receptors: On the intracranial vessels: Constricts Intracranial Blood Vessels leading to Closing shunts and Counteracts vasodilation during migraine attacks. Helps alleviate headache pain. On the presynaptic trigeminal neuron: Inhibition of trigeminal nerve innervating the blood vessels  Block the release of pro-inflammatory neuropeptides Migraine treatment: 5HT2 receptor partial agonists/antagonist 5-HT via 5HT2 receptors is thought to produce trigeminal nerve excitation, inflammation and vasodilation in some extracerebral vessels and hence can lead to migraine. Blockade of these receptors therefore reduces these features which underlie migraine. Pizotifen is a 5-HT2A-C receptor antagonist and also antagonizes histamine H1 receptor. Pizotifen is used prophylactically for prevention of attacks and is ineffective in an active migraine attack  5HT receptor antagonists as antiemetics Nausea and vomiting 5-HT release, primarily in the gastrointestinal tract and in the CNS, plays a key role in emesis (vomiting). Mediated mainly through 5HT3 receptors: In the vomit center in CNS Peripheral neurons in GI Clinical Implications: 5-HT3 Antagonists as Anti-emetic Drugs: Examples: Ondansetron, Tropisetron. Used to prevent nausea and vomiting associated with: Post-surgical operations. Chemotherapy treatments (acute nausea). Radiation treatments. Depression & Anxiety Monoamine Theory of Depression: Depression linked to a deficit of monoamine neurotransmitters (e.g., serotonin) in the limbic system. Goal: Increase neurotransmitter levels to alleviate symptoms. Selective Serotonin Reuptake Inhibitors (SSRIs): Mechanism: Block serotonin transporter (SERT), inhibiting 5-HT reuptake. Increase serotonin levels and enhance serotonergic neurotransmission. Uses: SERT Treat depression and anxiety disorders. 5-HT1A Receptor Partial Agonists: Mechanism: Act on 5-HT1A presynaptic inhibitory receptors. Enhance serotonergic activity. Uses: Effective for both depression and anxiety treatment.  Antipsychotic: Psychosis is associated with an increase in dopamine release in certain areas of the brain and a decrease in other areas leading to variety of positive and negative symptoms Clozapine: Blocking 5HT2A/2C at those different parts of the brain modulate the release of dopamine in psychosis: Increases the release of dopamine in the areas where they are undersecreted Decrease the release of dopamine in the areas where they are oversecreted Ergot alkaloids Ergot Alkaloids Pharmacodynamics: Are produced by Claviceps puruprea, fungus in grasses and grains Ergot alkaloid act on several types of receptors: α adrenoceptors, dopamine receptors, 5-HT receptors Some have postsynaptic and presynaptic effect Clinical use: Migraine Ergotamine Hyperprolactinemia Postpartum hemorrhage PPH Ergometrem Effect of ergot alkaloids on body systems: CNS: Ergots with activity on dopamine Bromocriptine, tuting Fine.ee High selectivity for pituitary dopamine receptors (agonist) Suppress prolactin secretion o Vascular smooth muscle: treat anosimx Effect vary based on drug, species, and vessel. vasoconstriction at nanomolar concentrations or O Effect on α1 receptor partial agonist – major, Partial agonist on 5-HT2 Example: ergotamine for the treatment of migraine Uterine smooth muscle: Ergonovine more uroselective agonist Due to effect on α1 receptor and 5-HT (serotonin) receptors on the smooth muscle (contraction) and vasoconstriction Effect increase dramatically during pregnancy (due to increase in α1 receptor)